Human Pathology (2014) xx, xxx–xxx

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Original contribution

The Fuhrman grading system has no prognostic value in patients with nonsarcomatoid chromophobe renal cell carcinoma☆ Sandra Steffens MD a,⁎,1 , Martin Janssen MD b,1 , Frederik C. Roos MD c,1 , Frank Becker MD d , Julie Steinestel MD e , Mahmoud Abbas MD f , Konrad Steinestel MD, PhD k , Gerd Wegener MD g , Stefan Siemer MD b , Joachim W. Thüroff MD c , Rainer Hofmann MD h , Michael Stöckle MD b , Mark Schrader MD e , Arndt Hartmann MD i , Andrea Hasenfus MD j , Markus A. Kuczyk MD a , Kerstin Junker MD b , Andres J. Schrader MD e,h , for the German Renal Cell Cancer Network a

Department of Urology and Urological Oncology, Hannover University Medical School, D-30625 Hannover, Germany Department of Urology and Pediatric Urology, Saarland University Medical Center and Saarland University Faculty of Medicine, D-66421 Homburg/Saar, Germany c Department of Urology, Mainz University Medical Center, D-55101 Mainz, Germany d Boxberg Centre, Urological Group and Clinic Derout/Pönicke/Becker, D-66538 Neunkirchen, Germany e Department of Urology, Ulm University Medical Center, D-89075 Ulm, Germany f Institute of Pathology, Hannover University Medical School, D-30625 Hannover, Germany g Cancer Center, Hannover University Medical School, D-30625 Hannover, Germany h Department of Urology, Philipps University of Marburg, D-35037 Marburg, Germany i Institute of Pathology, Erlangen University Medical Center, D-91023 Erlangen, Germany j Institute of Pathology, Saarland University Faculty of Medicine, D-66421 Homburg/Saar, Germany k Institute of Pathology, Bundeswehrkrankenhaus Ulm, 89081 Ulm, Germany b

Received 20 May 2014; revised 1 August 2014; accepted 5 August 2014

Keywords: Renal cell carcinoma; Fuhrman nuclear grading system; Histology; Chromophobe RCC; Prognosis; Survival

Summary The prognostic value of the Fuhrman nuclear grading system has been questioned for chromophobe renal cell carcinoma (chRCC) because this subtype frequently displays nuclear and nucleolar pleomorphism. The present study reevaluates this grading system in a series of patients with nonsarcomatoid chRCC. We identified 176 patients (3.6%) with nonsarcomatoid chRCC in a total of 4897 patients who underwent surgery for renal cell carcinoma at 5 centers in Germany between 1990 and 2010. The mean follow-up was 51.1 months. The 3 groups (G1 versus G2 versus G3/4) were comparable in terms of age, sex, tumor diameter, and lymph node metastasis. They only differed significantly in tumor stage (P = .01) and the incidence of synchronous visceral metastasis (P = .04). The 5-year cancer-specific survival rates were 84.4% for G1 (n = 32), 84.3% for G2 (n = 108), and



Disclosures: None. ⁎ Corresponding author. Department of Urology and Urological Oncology, Hannover University Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. E-mail address: [email protected] (S. Steffens). 1 These authors contributed equally. http://dx.doi.org/10.1016/j.humpath.2014.08.002 0046-8177/© 2014 Elsevier Inc. All rights reserved.

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S. Steffens et al. 74.1% for G3/4 tumors (n = 33) (P = .58). Accordingly, multivariate analysis including age, sex, tumor stage, and metastatic disease did not identify Fuhrman grading as an independent predictor of cancerspecific survival in patients with chRCC (P = .4). We were able to demonstrate in a large multicenter cohort that the Fuhrman grading system does not qualify as a prognostic tool in patients with chRCC. © 2014 Elsevier Inc. All rights reserved.

1. Introduction

Staging was based on the 2002 TNM classification [11] because most patients were treated during its period of validity. Institutional databases were searched for information on patient and tumor characteristics, such as age, sex, stage, regional lymph node involvement or distant metastases, histologic subtype, and Fuhrman grade. Three cases did not have exact Fuhrman grading and were excluded from further analysis. Furthermore, information about lymph node involvement and metastasis status was missing in 10 and 6 cases, respectively.

The TNM stage and tumor grade are currently the tools most widely used to predict survival in renal cell carcinoma (RCC). The Fuhrman grading system has been acknowledged as a prognosticator for the oncological outcome [1] and is widespread in pathology practice. It is based on the assessment of nuclear size, nuclear shape, and nucleolar prominence [2]. Fuhrman grading has been found to correlate with the risk of metastasis, the metastasis rate being significantly lower for grade 1 than for grade 2 to 4 tumors. Fuhrman et al [2] were able to show that survival rates can be grouped into 3 categories: those in grade 1, those in grade 4, and those in grades 2 and 3 RCC. However, the utility of Fuhrman grading has been questioned, and studies have highlighted problems relating to its application as initially proposed [3-5]. Moreover, the Fuhrman nuclear grading system was developed and validated mostly for clear cell and papillary RCC [2], and its value for chromophobe RCC (chRCC) has been discussed controversially. Because irregular nuclei, prominent nucleoli, and nuclear pleomorphism are inherent features of chRCC, the Fuhrman nuclear grade is often higher, although most of these tumors have a favorable outcome. A series of 87 chRCC patients published by Delahunt et al [6] concluded that neither Fuhrman grading nor any of its underlying components correlated with clinical outcome. This has been confirmed by 2 other studies [7,8]. In contrast, in 1 series of 103 chRCC patients, Fuhrman grading was shown to correlate with survival, although significance was lost in multivariate analysis [9]. In view of these inconsistent results, the aim of this large retrospective multicenter study was to systematically evaluate the prognostic value of the Fuhrman nuclear grading system in patients with nonsarcomatoid chRCC and a long clinical follow-up.

The χ2 or Fisher exact test was conducted to assess correlations between patient/tumor characteristics and the tumor grade according to the Fuhrman grading system. Continuous parameters were compared applying the Kruskal-Wallis test. Kaplan-Meier estimates of survival time were calculated, and subgroups were compared by the log-rank test. Multivariate Cox regression models were used to assess the association between survival and the Fuhrman tumor grade adjusted for different clinical and patient covariates (ie, age, sex, tumor stage, and metastatic status). SPSS 21.0 (SPSS, Chicago, IL) was used for statistical analysis. A 2-sided P b .05 was considered to indicate significance in all tests.

2. Patients and methods

3. Results

2.1. Patient and tumor characteristics

Our patient population of 99 men (56.3%) and 77 women (43.8%) had a median age of 61 years (interquartile range, 51.5-70.0). The median/mean follow-up was 43.0/51.1 months (interquartile range, 17.2-76.5). By the last day of data acquisition, 25 patients (14.2%) had died of cancer, and 11 (6.3%), of other causes. The exact Fuhrman grading was available for 173 patients (98.3%). Altogether, 32 chRCC patients (18.5%) were classified as G1; 108 (62.4%), as G2;

This retrospective study included 4897 patients who underwent RCC surgery in 1990 to 2010 with a total of 176 chRCC patients (3.6%) at Hannover, Homburg, Mainz, Ulm, and Marburg university medical centers. The histologic tumor subtype was determined according to the 1997 International Union Against Cancer classification [10].

2.2. Follow-up The duration of follow-up was calculated from the date of surgery to the date of death or last follow-up. Death was assessed as either cancer related or non–cancer related. The primary end point of this study was cancer-specific survival (CSS). Information about the exact date and cause of death of each patient was mostly obtained from hospital records or local cancer registries. Follow-up assessment ended in August 2013.

2.3. Statistical methods

Fuhrman grading system and chromophobe RCC F1

T1

and 33 (19.1%), as G3 or G4 (Fig. 1). Actually, only 1 patient was classified as G4; for further statistical analysis, he was integrated in the group of grade 3 patients. None of the patients had a tumor with sarcomatoid features. Detailed tumor and patient characteristics are summarized in Table 1.

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3.1. Clinical parameters Patients with chRCC of different tumor grades (G1 versus G2 versus G3) were comparable with respect to median age (P = .74, Kruskal-Wallis test) and sex (P = .67, χ2 test). There were no detectable differences related to the affected side or the occurrence of bilateral tumors (P = .71), clinical symptoms at diagnosis (P = .62), or the treatment by a nephron-sparing approach/radical nephrectomy (P = .54).

3.2. Tumor-specific parameters Patients with high-grade tumors suffered significantly more often from high-stage cancer (P = .01, χ2 test) or visceral metastasis (P = .04; Table 1). Accordingly, highgrade cancer was significantly associated with advanced disease (pT3-4 and/or N1 and/or M1) at diagnosis: 3.2%, 17.8%, and 44.4% for G1, G2, and G3 chRCC, respectively (P = .001, χ2 test). The median tumor diameter, however, did not differ significantly between the 3 grading groups (P = .09, Kruskal-Wallis test).

3.3. Clinical course and oncological outcome The 5-year CSS and overall survival for the total cohort was 82.7% and 77.1%, respectively. The 5- and 10-year CSS rates of all evaluable patients were 84.4% and 73.8% for G1 (n = 32), 84.3% and 75.2% for G2 (n = 108), and 74.1% and 74.1% for G3-4 tumors (n = 33) (P = .58, log-rank test; Fig. 2). Accordingly, the 5- and 10-year overall survival rates were 78.1% and 68.4% for G1, 77.6% and 64.9% for G2, and 74.1% and 74.1% for G3 tumors (P = .77, log-rank test). Multivariate analysis including age, sex, tumor stage, nodal/visceral involvement, and tumor differentiation revealed that—unlike age (P = .002), local tumor stage (P = .02), and metastatic status (P = .02)—Fuhrman grading did not qualify as an independent prognostic factor for patients with chRCC (P = .40, Cox regression analysis; Table 2).

4. Discussion

Fig. 1 Examples for the Fuhrman grading system: grade 1 (A), grade 2 (B), and grade 3 (C).

In the original report by Fuhrman et al [2] in 1982, grading was validated in a series that included clear cell RCC, papillary RCC, and tumors with mixed histology. When dividing Fuhrman grading into low- and high-grade tumors, an association with survival was regularly confirmed in subsequent studies involving mainly clear cell RCC [1215]. However, the interobserver reproducibility for Fuhrman grading is poor due to the highly subjective nature of the grading process. Furthermore, its relevance to other histologic subtypes of RCC is still controversially discussed. Interestingly, the utility of Fuhrman grading for RCC in general was questioned by the International Union Against

F2

T2

4

S. Steffens et al. Table 1

Association between different patient/tumor variables and Fuhrman grading in patients with chRCC

Variable a

Age, median (y) Sex Female Male Stage pT1a pT1b pT2 pT3a pT3b pT4 Tumor diameter, median (cm) Lymph node involvement a N0 N1 Pulmonary/visceral metastasis a M0 M1 a

G1

G2

G3

P

Test

59.5

62.0

59.0

.74 .67

Kruskal-Wallis χ2

.01

χ2

.09 .32

Kruskal-Wallis χ2

.04

χ2

15 (46.9%) 17 (53.1%)

44 (40.7%) 64 (59.3%)

16 (48.5%) 17 (51.5%)

19 (59.4%) 10 (31.3%) 2 (6.3%) 0 1 (3.1%) 0 3.6

41 (38.0%) 29 (26.9%) 20 (18.5%) 11 (10.2%) 7 (6.5%) 0 5.0

11 (33.3%) 6 (18.2%) 4 (12.1%) 6 (18.2%) 4 (12.1%) 2 (6.1%) 5.0

31 (100%) 0

99 (93.4%) 7 (6.6%)

25 (96.2%) 1 (3.8%)

31 (100%) 0

102 (95.3%) 5 (4.7%)

25 (86.2%) 4 (13.8%)

At the time of renal cancer surgery.

Cancer Workgroup on Grading of Renal Cell Carcinoma as early as in 1997 [5]. However, for lack of conclusive studies at that time, it was suggested that the Fuhrman system should continue to be used for all subtypes, including chRCC. chRCC comprises 2.1% to 11% of RCCs [16]. Although it often has a better clinical outcome than clear cell RCC [8], studies assessing prognostic factors for this RCC subtype are limited by the infrequency of tumor-related deaths and the small number of patients included in most of the series published. The present study includes 176 nonsarcomatoid chRCC patients with a long-term clinical follow-up and is

thus, to our knowledge, one of the largest cohorts published so far. In an interesting study presented by Kim et al [17] in 2004, a high tumor grade was found to be significantly associated with shorter survival in 70 chRCC patients; on multivariate analysis, however, this significance was lost when cases were stratified according to treatment modality, TNM stage, and sarcomatoid differentiation [17]. Somewhat

Table 2 Multivariate analysis did not identify Fuhrman grading as an independent predictor of cancer-specific survival in patients with chRCC Variable a

Fig. 2 CSS (Kaplan-Meier) plotted against the Fuhrman grade for 176 evaluable patients with chRCC. The 5- and 10-year survival rates of all evaluable patients were 84.4% and 73.8% for G1 (n = 32), 84.3% and 75.2% for G2 (n = 108), and 74.1% and 74.1% for G3-4 tumors (n = 33) (P = .58, log-rank test).

Age (y) Sex Female Male T stage pT1a pT1b pT2 pT3a pT3b pT4 Metastasis a N/M0 N/M1 Differentiation G1 G2 G3

P

HR (95% CI)

.002 .84

1.08 (1.03-1.16) 1 (Reference) 0.91 (0.35-2.33)

.02 .58 .92 .006 .02 .99 .02

1 (Reference) 0.65 (0.14-3.10) 0.89 (0.09-8.85) 8.34 (1.85-37.61) 6.17 (1.28-29.85)

1 (Reference) 3.58 (1.21-10.59) .40 .20 .50

1 (Reference) 0.39 (0.09-1.63) 0.54 (0.09-3.31)

Abbreviations: CI, confidence interval; HR, hazard ratio. a At the time of surgery.

Fuhrman grading system and chromophobe RCC surprising, Patard et al [9] found a more favorable outcome for Fuhrman grade 3 and 4 than for grade 1 and 2 tumors in a study including 102 chRCC patients. This finding underscores the problematic nature of applying Fuhrman grading criteria to this RCC subtype. In a study evaluating 87 chRCC patients, Delahunt et al [6] found that neither the Fuhrman grading system nor any of its components (uniformity of nuclear size, nuclear shape, and nucleolar prominence) correlated with outcome. Finally, Paner et al [7] showed that Fuhrman grading failed to independently predict clinical outcome in 102 nonsarcomatoid chRCC patients. The results obtained in our large multicenter study are in line with these findings. Although high Fuhrman grades were associated with an advanced stage of chRCC, we were able to show by univariate and multivariate analyses that Fuhrman grading is no suitable prognosticator for cancerspecific or overall survival in nonsarcomatoid chRCC. Thus, we could confirm earlier results from a univariate analysis presented by Przybycin et al [8], who evaluated 197 nonsarcomatoid chRCC patients. Surprisingly, Fuhrman grading did, in fact, correlate with tumor stage in our study, although it was not associated with any other patient or tumor characteristic. One possible explanation for significantly higher tumor grades being associated with advanced disease (pT3-4 and/or N1 and/or M1) but not with clinical outcome could be that knowledge of the tumor stage might have influenced the subjective assignment of Fuhrman grades by some pathologists. Another reason could be that, although higher Fuhrman grades are actually associated with advanced tumor stages, they are not associated with poor clinical outcome in the chRCC subtype and, therefore, have no prognostic value in chRCC. This is supported by the fact that chRCC often has an inconspicuous nucleolus inconsistent with the degree of nuclear pleomorphism they usually exhibit. The assigned grade thus depends on the significance individual pathologists attach to these defining features when applying Fuhrman criteria to chRCC. Accordingly, Paner et al [7] developed a novel grading system for chRCC based on nuclear crowding and anaplasia. They used this system as an independent predictor of survival in 102 patients with nonsarcomatoid chRCC. Applying the grading system described by Paner et al [7], however, neither Cheville et al [18] nor Przybycin et al [8] were able to confirm a significant association with outcome in larger patient cohorts. Therefore, these authors suggested that classic grading, although appropriate for other RCC subtypes, might not be useful for chRCC. Only last year, the “International Society of Urological Pathology Grading System for Renal Cell Carcinoma and Other Prognostic Parameters” has agreed that, until further data have been accumulated, chRCC should not be graded at all [19]. This decision was based mainly on the study by Delahunt et al [6] suggesting that Fuhrman grading appears to be inappropriate for chRCC due to the inherent nuclear atypia of this RCC subtype.

5 Our study has several important limitations. First and foremost are those inherent in retrospective analysis, the lack of central pathology review, and a multicenter setting. However, the fact that all centers have significant experience in RCC management may increase the external validity of the data compared with a single-center setting. Moreover, our study population included only nonsarcomatoid chRCC patients. Sarcomatoid features in any RCC subtype have been associated with aggressive growth patterns and extremely poor clinical outcome. The varying proportion of tumors with sarcomatoid differentiation in the studies by Przybycin et al [8], Paner et al [7], Amin et al [20], and Cheville et al [18] of 2% 10%, 8%, and 7%, respectively, could have significantly influenced the results of each of these studies and may explain the divergent outcomes. In conclusion, the Fuhrman nuclear grading system did not qualify as an independent predictor of CSS for chRCC patients in this study. Therefore, our findings—which are supported by earlier investigations and the current International Society of Urological Pathology recommendations— confirm that the Fuhrman grading system is of questionable value for nonsarcomatoid chRCC and should be abandoned. Further work is required in terms of developing a prospective validated grading system adapted to histologic characteristics of chRCC or, better yet, finding molecular markers that correlate with chRCC aggressiveness and prognosis.

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S. Steffens et al. [16] Vera-Badillo FE, Conde E, Duran I, et al. Chromophobe renal cell carcinoma: a review of an uncommon entity. Int J Urol 2012;19:894-900. [17] Kim H, Cho NH, Kim DS, et al. Renal cell carcinoma in South Korea: a multicenter study. HUM PATHOL 2004;35:1556-63. [18] Cheville JC, Lohse CM, Sukov WR, et al. Chromophobe renal cell carcinoma: the impact of tumor grade on outcome. Am J Surg Pathol 2012;36:851-6. [19] Delahunt B, Cheville JC, Martignoni G, et al. The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters. Am J Surg Pathol 2013; 37:1490-504. [20] Amin MB, Paner GP, Alvarado-Cabrero I, et al. Chromophobe renal cell carcinoma: histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 145 cases. Am J Surg Pathol 2008;32:1822-34.

The Fuhrman grading system has no prognostic value in patients with nonsarcomatoid chromophobe renal cell carcinoma.

The prognostic value of the Fuhrman nuclear grading system has been questioned for chromophobe renal cell carcinoma (chRCC) because this subtype frequ...
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